PNU-140690 is a new nonpeptidic HIV protease inhibitor (PI) effect against ritonavir/indinavir resistant HIV isolate in vitro. Methods: Open-label, multiple-doses (900, 1200 and 1500mg TID) of PNU-140690 were administered to 24 PI naive patients, who had CD4 cell > 50 cells/mm3, HIV RNA >4000 copies/mL, and were on stable dual nucleoside reverse transcriptase inhibitors (NRTIs) for >2 months (median - 10 months). Pharmacokinetic parameters were estimated from steady-state profiles obtained on study day 10. Primary immunological and virological parameters for efficacy were CD4 and plasms HIV-1 RNA measured by Roche's Amplicor and ultrasensitive assay. Results: Data collected up to 4 weeks showed that PNU-140690 was well tolerated. No serious adverse events (AE) reported. Primary AEs were gastrointestinal (GI) tract related including diarrhea, nausea and vomiting that were managed by taking study drug with light snacks, although 37% were treated symptomatically. Steady-state trough PNU-140690 concentration on day 10 averaged 1.2+ or - 0.6, 1.9 + or - 1.2, and 2.8 + or - 1.6 micromolar in the 900, 1200, and 1500mg TID troups, respectively. Adding PNU-140690 to dual NRTI therapy resulted in mean HIV RNA reduction of 1.0, 1.3, and 1,2 log on day 11 in the 900, 1200, and 1500 mg TID groups respectively. At week 4 the corresponding average RNA reductions were 0.5, 1.1, and 0.9 logs in these groups. No genotypic changes observed at week 4. Clinical records suggested compliance was correlated with the changes in HIV RNA levels. Conclusions: PNU-140690, a new nonpeptidic HIV protease inhibitor with potent antiretroviral effect has been well tolerated in PI naive patients in this study at doses of 900 to 1500 mg TID. There were no significant adverse effects of PNU-140690 observed when PNU-140690 was added to stable dual NRTI therapy. The pahamacokinetics of PNU-140690 taken with two NRTIs in HIV-1 infected patients were similar to those observed in healthy volunteers receiving PNU-140690 alone.